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Corticosteroid injections are commonly indicated in inflammatory conditions involving the soft tissues, tendon sheaths, bursae, and joints. Local corticosteroids carry a lower risk of complications than systemic corticosteroid but may be systemically absorbed and subsequently suppress the hypothalamic-pituitary-adrenal (HPA) axis. This can cause secondary adrenal insufficiency (SAI) as well as iatrogenic Cushing’s syndrome. We report a 78-year-old female who presented with nonspecific gastrointestinal symptoms after a recent intra-articular steroid injection in her shoulder. She had hyponatremia, low morning cortisol, and failed to respond to high-dose cosyntropin. Further workup revealed the underlying cause to be SAI. Follow-up testing revealed a recovery of HPA responsiveness within 2 weeks of her initial diagnosis. Conclusion. Our case highlights how the hypothalamic-pituitary axis (HPA) can be suppressed with intra-articular steroids. The threshold to test corticosteroid users for adrenal insufficiency should be low in clinical practice, especially for those patients with nonspecific symptoms after steroid injections. Once diagnosed, temporary treatment with steroids may be required.

Objective To assess the impact of using corrected calcium versus total calcium on hypercalcemia case detection in hospitalized patients. Methods Patients hospitalized from June 2012 to June 2017 with a corrected calcium level of ≥10.5 mg/dL were identified by medical record review. One-year follow-up data through June 2018 were acquired. Albumin-corrected calcium level was calculated: (4 − albumin concentration in g/dL) × 0.8 + total serum calcium in mg/dL. Results A group of 1067 patients had a corrected calcium level of ≥10.5 mg/dL. The prevalence of hypercalcemia was 0.73% with total calcium and 1.09% with corrected calcium, respectively, with a 49% relative increase. Most patients (62%) had mild hypercalcemia (10.5-11.9 mg/dL); 3.7% had severe hypercalcemia (>14 mg/dL). With corrected calcium, the most common categories of hypercalcemia were malignancy (35.4%), hypercalcemia that was not further evaluated (31.1%), and hyperparathyroidism (22.4%). All patients in the unidentified category had albumin levels Conclusion Using albumin-corrected calcium resulted in an ∼50% increase in the detection of hypercalcemia cases. Although hypercalcemia resolved in majority of the undiagnosed cases at 1 year, a number of these remained abnormal. Detecting hypercalcemic disorders by correcting for low albumin level can help identify conditions such as hyperparathyroidism. Adding auto-calculated albumin-corrected calcium to routine laboratory tests could be a cost-effective intervention to improve the detection of hypercalcemic disorders.

Inhaled glucocorticoids (ICS) are recommended in all patients with persistent asthma. While relatively safe, ICS can occasionally cause systemic side effects including adrenal suppression, bone loss, and cataract formation. We describe a 53-year-old woman with adrenal insufficiency secondary to inhaled fluticasone. A 53-year-old woman was referred for evaluation of an incidental 5.5×2.7 cm left adrenal mass discovered on CT chest when she was hospitalized for an asthma exacerbation. She had asthma since the age of 20 and had intermittently been on oral steroids which were tapered off several months prior to her evaluation. Medications included fluticasone (230-21mcg/actuation inhaler) HFA 2 puffs twice daily, azithromycin, azelastine, calcium carbonate, cholecalciferol, esomeprazole, guaifenesin, magnesium, and montelukast. On exam vital signs were: BP 128/88, HR 95, BMI 41.13 kg/m2. She was obese with left > right supraclavicular fullness, mild dorsocervical fullness, slightly thinned skin, but no striae or proximal muscle weakness. Labs were initially sent to evaluate for an adrenal incidentaloma: A random morning (8 AM) cortisol was She was diagnosed with adrenal insufficiency likely caused by an exogenous steroid. Since she had been off oral steroids for several months urinary steroid testing was performed revealing an elevated fluticasone metabolite: Fluticasone 17β-carboxylic acid >10,000 pg/nL (nl < 10 pg/nL). Hence inhaled fluticasone was determined to be the cause. Similar findings have been described in patients with HIV on anti-retroviral therapy (ART) where metabolism of inhaled steroids can be impaired resulting in hypothalamic-pituitary-adrenal suppression. Our patient was not on ART but may have a genetic variant resulting in delayed steroid clearance or enhanced susceptibility to HPA suppression, though fluticasone is known to accumulate in adipose tissue. She stopped fluticasone and several days later repeated urine testing revealing a urine Fluticasone 17β-carboxylic acid level of 96 pg/nL, two weeks later inhaled budesonide was initiated and over the course of three months her ACTH increased from 3.3 to 18.3 to 26.3 (pg/mL) and cortisol rose slightly from 0.9 to 3.2 to 3.7 mcg/dL. Conclusion Awareness of the potential systemic side effects of inhaled corticosteroids is important and patients should be kept on the lowest effective dose. Conversely, in the evaluation of patients with secondary adrenal insufficiency the possibility of inhaled corticosteroids playing a causative role should be considered. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Introduction Levothyroxine malabsorption is one of the causes of refractory hypothyroidism. Administration of a single large dose of levothyroxine can help distinguish this from refractory hypothyroidism due to other causes, but little is known about the utility of this test in patients hospitalized for severe hypothyroidism. Case 1 A 42-year-old woman with Hashimoto's thyroiditis presented with symptomatic hypothyroidism. She reported being compliant with 150 mcg of levothyroxine daily. However, in the past year, her free T4 remained < 0.10 ng/dL on several occasions with TSH > 80 uIU/mL. On admission, free T4 was 0.58 ng/dL, total T4 was 4.9 ug/dL, and TSH was 57.06 uIU/mL. We administered 1000 mcg levothyroxine and found an increase in total T4 at 4 hours (12.1 ug/dL from 4.9 ug/dL). Absorption was found to be 100% at 4 hours implying that she was not taking her levothyroxine appropriately. She was counseled to take levothyroxine at 150 mcg on an empty stomach. At outpatient follow up in 3 weeks, free T4 improved to 1.44 ng/dL and TSH decreased to 1.050 uIU/mL. Case 2 A 42-year-old woman with hypothyroidism, alcohol hepatitis, chronic pancreatitis and previous Roux-en-Y gastric bypass was admitted with progressive lower extremity edema and shortness of breath. She reported taking levothyroxine 175 mcg each morning with her other medications that included omeprazole and magnesium oxide, along with coffee and milk soon after. Her admission labs showed free T4 0.61 ng/dL, total T4 2.8 ug/dL and TSH 84.4 uIU/mL. After 1000 mcg of levothyroxine her total T4 increased from 2.6 ug/dL to 7.8 ug/dL in 4 hours, indicating 100% absorption. The reason for her inadequate outpatient response was probably the combined use of omeprazole, magnesium oxide and coffee with milk, being taken with levothyroxine. She was asked to continue levothyroxine 150 mcg on an empty stomach. Method: Patients were made NPO at midnight prior to the morning of the study. Baseline total T4 was obtained at 6: 00 AM and 1000 mcg of oral Levothyroxine was administered while the patient was monitored on telemetry. Total T4 was measured at 2 and 4 hours after administration. Percentage absorption (% absorbed) = [[Increment TT4 (mcg/dL)×10 (dL/L)]/[total administered LT4 (mcg)]]×Vd (L)X100; Increment TT4 = [Peak TT4] - [Baseline TT4]; Vd (volume of distribution) = 0.442×BMI1 Conclusion These cases indicate that a 1000 mcg T4 absorption study is safe and reasonable to perform in patients who are hospitalized for profound hypothyroidism when outpatient evaluation has been ineffective or challenging. 1 Gonzales KM, Stan MN, Morris JC 3rd, Bernet V, Castro MR. The Levothyroxine Absorption Test: A Four-Year Experience (2015-2018) at The Mayo Clinic. Thyroid. 2019 Dec;29(12): 1734-1742. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Background Alpelisib is an oral α-specific phosphatidylinositol 3-kinase (PI3K) inhibitor use in combination with fulvestrant to treat postmenopausal women with HR+/HER2−, PIK3CA-mutated, advanced or metastatic breast cancer that has acquired resistance to endocrine-based therapy. (1)Alpelisib interferes with the PI3K/Akt signalling pathway resulting in impaired peripheral glucose uptake, increased liver glycogenolysis, loss of beta-cell mass and insulin secretion dysfunction(2). Hyperglycemia is a frequent adverse effect of alpelisib but diabetic ketoacidosis (DKA) is considered a rare occurrence. We describe a patient without a previous history of diabetes who developed DKA after 2 months on alpelisib.Clinical caseA 81 year-old woman with metastatic ER+ PR – Her2 - breast cancer, presented with a 1 week history of nausea, vomiting, and polyuria. Her hemoglobin A1C was 5.5% on two separate occasions last year. She had started alpelisib at 300 mg/day 7 weeks prior to presentation. She presented with a blood glucose (BG) of 659 mg/dL, anion gap of 21, serum bicarbonate 17 mmol/L, beta-hydroxybutyrate 3.82 mmol/L (normal < 0.27 mmol/L), serum osmolarity 319 mOsm/kg, serum creatinine 2.83 mg/dL (baseline 1.38 mg/dL), C-peptide 4.3 ng/mL (normal 1.1–4.4 ng/mL), negative GAD-65 antibodies and Islet Antigen 2 antibodies, septic workup were non-revealing, leading to the diagnosis of alpelisib-associated DKA. Alpelisib was held, and she was treated with intravenous insulin and hydration. DKA resolved in 12 hours, however, she had persistent hyperglycemia. She was started with insulin regimen of 0.2 units/kg and discharged with Humalog 75/25 5 units twice daily. Conclusion Patients with no pre-existing history of diabetes mellitus can also be at risk for DKA which may develop within weeks to months of initiation of alpelisib. Risk factors for development of DKA are yet to be identified, but would be useful to help tailor frequency of BG monitoring. This warrants further research. The hyperglycemic effects of alpelisib appear to be reversible upon drug discontinuation, however when DKA is the presenting syndrome, insulin therapy is indicated. Reference André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20): 1929-1940. doi: 10.1056/NEJMoa1813904. PMID: 31091374. Nguyen P, Musa A, Samantray J. Alpelisib-Induced Diabetic Ketoacidosis. Cureus. 2021 May 1;13(5): e14796. doi: 10.7759/cureus.14796. PMID: 34084688; PMCID: PMC8166359. Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

Rare cases of pancreatic neuroendocrine tumors (PNETs) that produce only proinsulin (PI) and manifest with hypoglycemia have been reported. Proinsulin expression in PNET has not been systematically studied, and the clinicopathologic features of such tumors remain unknown.We studied expression of PI by immunohistochemistry (IHC) in 136 PNETs from 2 high-volume surgical oncology centers and assessed all available clinicopathologic data.Thirty-six (26%) of PNETs were positive for PI by IHC, most (89%) of which coexpressed insulin IHC. Nine PI-positive tumors represented functional insulinomas. Patients with PI IHC-positive tumors demonstrated significantly lower mean preoperative serum glucose compared with PI-negative PNET patients, even when insulinomas were excluded. No differences in survival between PI IHC-positive and PI IHC-negative tumors were observed. We identified 2 PI-positive PNETs from hypoglycemic patients, which were not insulinomas or other functional variants and in which serum PI was never tested. These may have been undetected proinsulinomas.Proinsulin-expressing PNETs (functional or non) are not uncommon. Patients who present with hypoglycemia and normal insulin levels should be screened for proinsulinoma. Proinsulin IHC could also be used to screen for proinsulinoma. To further elucidate the clinical significance of PI expressing PNETs, prospective studies are required.

Patient: Female, 37-year-old Final Diagnosis: Diabetic ketoacidosis • Fournier’s gangrene Symptoms: Dysuria • pain Medication: Canagliflozin Clinical Procedure: Incision and drainage Specialty: Endocrinology and Metabolic • General and Internal Medicine Objective: Adverse events of drug therapy Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors have become an appealing treatment for diabetes due to their favorable cardiac and renal outcomes. However, reports continue to emerge describing potentially life-threatening adverse events such as Fournier’s gangrene and diabetic ketoacidosis associated with their use. Herein, we present a case of simultaneous Fournier’s gangrene and diabetic ketoacidosis after initiation of treatment with canagliflozin. Case Report: A 37-year-old female with diabetes presented to the hospital with a chief complaint of left gluteal pain associated with dysuria 1 month after canagliflozin was added to her regimen. On initial evaluation, the patient was afebrile and hemodynamically stable. Physical examination revealed suprapubic tenderness and induration in the left gluteal region extending to the perineum. Laboratory testing was significant for anion gap metabolic acidosis with the presence of serum ketones. Computed tomography of abdomen and pelvis revealed features suggestive of Fournier’s gangrene. The patient was treated for Fournier’s gangrene and diabetic ketoacidosis. Management included empirical antibiotic treatment, multiple surgical explorations with debridement as well as insulin infusion with aggressive fluid resuscitation. The patient was discharged with a urinary catheter, vacuum dressing, and colostomy with instructions to start a basal bolus insulin regimen and discontinue canagliflozin. Conclusions: This is the first case describing a simultaneous occurrence of Fournier’s gangrene and diabetic ketoacidosis with SGLT2 inhibitor therapy. Considering the growing popularity of these drugs, it is important to be aware of their more serious and potentially fatal complications. It is also important to promptly terminate SGLT2 inhibitors when harmful adverse effects are suspected.

Background Unintentional weight loss, ascites, and altered mental status typically raise concerns for hepatologic-cardiac-oncologic disease. Herein we present a case that after exhaustive workup the etiology of the aforementioned findings was attributed to a combination of anorexia and severe hypothyroidism, states where slowed metabolism and altered nutritional status can interact synergistically. Clinical Case A 71 y/o lady with a history of hypothyroidism after RAI for Graves’ disease, anxiety, depression, presented with 20-30 lbs unintentional weight loss over 5 months. She had poor appetite, nausea, constipation, increased abdominal girth, anasarca, fatigue, weakness, and altered mental status. On exam she had bradycardia, hypotension and hypothermia (BP 97/51, HR 54, RR 18, Temp 94, BMI 15.8). Labs revealed a TSH of 36, FT4 0.98, Tbili 0.3, alk phos 491, AST 435, ALT 651, gGT 151, albumin 2.3, prealbumin 14.7, INR 1.03, and pancytopenia. Treatment with IV levothyroxine resulted in mental status improvement. Over the next few months extensive testing revealed mild element deficiencies (zinc 44- nl range 60 - 130 mcg/dL, vit A 32- nl range 38 - 98 mcg/dL), no evident infectious/hematologic or inflammatory disease. Despite 3 paracenteses, 2 liver biopsies, multiple imaging studies (abdominal U/S, ECHO, XRs, CT chest/abdomen/pelvis, MRI abdomen/pelvis, enterography, MRI brain, PET scan), EGD/colonoscopy, bone marrow bx, and explorative laparoscopic abdominal surgery, no clear explanation was found. During the workup her liver enzymes remained elevated, TSH and fT4 normalized, but T3 remained low at 50 (76 - 181 ng/dL). Psychiatric evaluation revealed mild cognitive impairment, presumed to be secondary to depression and underlying disease. By exclusion, she was diagnosed with anorexia with a possible component of persistent hypothyroidism. She was fed through NG tube and followed closely by nutrition with a personalized high protein and calorie meal plan. Eight months later she had gained 5 lbs, her liver enzymes/electrolytes and CBC normalized, and most of her symptoms resolved. Conclusion Hypothyroidism can cause LFT abnormalities, and though rare, there are >50 cases of hypothyroidism induced ascites reported. Usually LFTs and ascites normalize promptly with hormone supplementation. However, our patient’s case was complicated by severe anorexia, with nutritional status essentially equivalent to kwashiorkor sufferers. Though extremely rare in the developed world and in adults, kwashiorkor like physiology has been described in patients with anorexia, with impressive liver abnormalities, presumed to be due to autophagy. Though certainly this is a rare diagnosis, it does point to the fact that in our test driven culture, it is worth pausing, re-evaluating history and physical and thinking outside the box prior to subjecting our patients to countless tests and procedures.

Background Nearly 25% of adrenal Cushing syndrome (CS) patients with bilateral adrenal masses have unilateral hypercortisolism, making localization crucial for surgical planning. Since there is no standardized protocol for adrenal venous sampling (AVS) in lateralizing adrenal hypercortisolism, we share our experience with a case of CS with bilateral adrenal masses in which lateralization via AVS permitted unilateral adrenalectomy. Clinical Case A 59-year-old woman with hypertension, hyperlipidemia, and prediabetes was hospitalized for worsening back pain and hypertension. Her BMI was 26.5 kg/m2, BP 173/93 mmHg, HR 73/min, she was anxious, diaphoretic, and hirsute. Glucose was 118 mg/dL and HbA1c 6.6%. Abdominal computed tomography revealed a type B aortic dissection with both right (6.1 x 3.1cm and 3.6 x 2.4cm), and left (largest 1.7 cm) sided adrenal masses. Plasma and 24 hour-urine metanephrine, normetanephrine and catecholamines, as well as plasma renin and aldosterone levels, were normal. AM cortisol on three different occasions was 21.30, 20.70, and 21.30 mcg/dL. Midnight cortisol was 17.8 mcg/dL, and 24-hour urine free cortisol on two occasions was 163 mcg (urine volume 3.4L with creatinine 1.14) and 99.2 mcg (urine volume 1.15L). After 1mg dexamethasone her AM ACTH and cortisol were

Introduction Sodium glucose co-transporter 2 (SGLT2) inhibitors have become an appealing treatment for diabetes due to their favorable cardiac and renal outcomes. However, reports continue to emerge describing potentially life-threatening adverse events such as Fournier’s gangrene (FG) and diabetic ketoacidosis (DKA) associated with their use. Herein, we report a case of simultaneous FG and DKA in a patient taking canagliflozin. Case Presentation A 37-year-old woman with a history of type 2 diabetes mellitus, peripheral neuropathy, and morbid obesity (BMI of 45.8 kg/m2) presented to the hospital with left gluteal pain associated with dysuria despite 5-day treatment with trimethoprim/sulfamethoxazole for a presumed urinary tract infection. Approximately 1 month prior, sitagliptin and canagliflozin were added to her regimen due to poor glycemic control on metformin (HbA1c 9.8%). On examination her temperature was 36.9oC, pulse 117 beats/minute, blood pressure 144/79 mmHg and respiratory rate was 19 bpm. She appeared lethargic and had suprapubic tenderness and induration in the left gluteal region extending to the perineum. Laboratory findings revealed an arterial pH of 7.23 and PCO2 of 34 mmHg, a blood glucose of 402 mg/dL, serum bicarbonate 12mmol/L (20-30mmol/L), an elevated anion gap of 24mmol/L (7-17mmol/L) and a lactate of 1.8 mmol/L. Urinalysis showed 4+ glucose and 1+ ketones. Serum β-hydroxybutyrate was 2.49 mmol/L (0.02-0.27mmol/L). A CT scan of the abdomen and pelvis showed marked inflammatory changes with subcutaneous edema and air within the medial left gluteal soft tissues and locules of air extending into the presacral soft tissues suggestive of Fournier’s gangrene. The diagnoses of Fournier’s gangrene and DKA were made. The patient was started on empirical antibiotic treatment and required six surgical explorations with debridement. Interestingly, initial DKA management included only subcutaneous insulin. Only when serum ketones were identified and the anion gap persisted, insulin infusion with aggressive fluid resuscitation was initiated with successful resolution of anion gap metabolic acidosis. She was discharged with a urinary catheter, vacuum dressing, colostomy with instructions to start insulin glargine 18U and discontinue the oral anti-diabetic medications. Discussion To the best of our knowledge, this is the first case describing the simultaneous occurrence of two potentially fatal adverse effects of SGLT2 inhibitor therapy; Fournier’s gangrene and DKA. In light of the FDA’s warnings and the growing popularity of SGLT2 inhibitor therapy it is important to be mindful of their more serious and potentially fatal complications. It is also important to promptly terminate SGLT2 inhibitors when harmful adverse effects are suspected to prevent further progression.

Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of islet cell-derived neoplasms with a propensity toward hormone production. Among PNETs, proinsulin-secreting tumors (proinsulinomas) are exceedingly rare. The objective of this study is to collect and summarize the existing literature to provide a comprehensive evaluation of this uncommon disease. A systematic review was performed to characterize the clinicopathologic features of proinsulinoma. Using the electronic biomedical databases PubMed, Ovid Medline, and Embase, 316 publications were screened for relevance of which 14 were selected. We also present two patients with proinsulinoma treated at Yale New Haven Hospital. Of the 16 patients included in the study, the mean age was 56.8 and there was a 2:1 female predominance. The majority of patients presented with symptomatic hypoglycemia with normal or low insulin levels. Median tumor diameter was 1.2 cm and 80% were located in the body and tail of the pancreas. Following resection, most patients had normalization of hormonal levels without recurrence (75%; 12/16). Proinsulinomas are rare pancreatic neuroendocrine tumors that have the potential to cause hypoglycemia. While insulinomas and proinsulin-secreting tumors have many physiologic parallels, these cases illustrate several key distinctions in their diagnosis and management.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant cause of familial hyperparathyroidism associated with benign, ossifying fibromas of the maxillofacial bones and increased risk of parathyroid carcinoma. The putative tumor suppressor gene CDC73 has been implicated in the syndrome, with a multitude of inactivating mutations identified; however, HPT-JT due to large-scale deletion of the chromosomal region containing the gene is exceedingly rare, and the clinical significance of this variant remains unclear. We report the case of a 32-year-old woman with a history of mandibular ossifying fibroma who presented with primary hyperparathyroidism and was found to harbor a large-scale, germline deletion on chromosome 1q31, including the CDC73 locus. HPT-JT is associated with loss of function of the putative tumor suppressor gene CDC73. Over 100 mutations and small insertions/deletions have been identified within the gene, the majority of which result in premature truncation of the parafibromin protein product. We report a case of HPT-JT associated with a large chromosomal deletion (4.1 Mb) encompassing the CDC73 gene locus. In the future, molecular testing in this autosomal dominant disorder should use techniques that allow for the detection of large-scale deletions in addition to the more commonly observed mutations and smaller-scale copy number alterations. Further investigation is needed to determine whether HPT-JT associated with a large-scale deletion carries increased risk of malignancy relative to the more common truncating mutations and what the implications are for genetic counseling., A case of hyperparathyroidism-jaw tumor syndrome associated not with a point mutation, but rather with a large chromosomal deletion encompassing the CDC73 gene locus.

Introduction Pembrolizumab, a humanized anti-programmed death -1 antibody has been used in the treatment of several malignancies with improved prognosis, but it has been associated with several immune related adverse effects, particularly endocrinopathy. We report a case of pembrolizumab induced isolated ACTH deficiency and resultant adrenal insufficiency in a 77-year-old woman who received immunotherapy for adenocarcinoma of the lung. Case report A 77-year-old woman presented to the hospital with fatigue and worsening shortness of breath. She had a history of stage IV non-small cell carcinoma lung for which she received pembrolizumab for a year, last dose 1 month prior to admission. She denied any long-term exposure to steroids except for a steroid cream which she used for 2 or 3 weeks several weeks before presentation. Her blood pressure was 130/70, pulse 80/min, rest of the physical examination was unremarkable. Labs were significant for Na 127mmol/L, K 4.2 mmol/L, blood glucose of 89 mg/dL, cortisol

Background Leptin is an adipocyte-derived peptide hormone that acts in the hypothalamus to stimulate pathways that inhibit feeding and promote energy expenditure. Mutations in the gene encoding leptin or its receptor (LR) are rare and typically lead to extreme obesity. We describe a patient who presented with severe hypertriglyceridemia, non-alcoholic fatty liver (NAFL) and a clinical phenotype of partial lipodystrophy, who upon whole exome sequencing harbored a novel homozygous mutation in the Ig domain of the LR. Clinical case A 45-year-old woman with a past medical history of hypertension presented with abdominal pain and was diagnosed with hypertriglyceridemic pancreatitis. She denied alcohol or recreational drug use. Her BMI was 26 kg/m2, BP 167/109 mmHg, HR 106, and she had prominent central obesity with a paucity of adipose tissue on the extremities and gluteal region. Triglycerides (Tg) were 2,076 mg/dl, lipase 366 u/l, A1c of 6.0%, ALT 70 u/l, AST 27 u/l. Proteinuria was present, but serum and urine protein electrophoreses were normal. Abdominal CT was suggestive of liver steatosis and pancreatitis. Given her lipodystrophic features, elevated Tg, and fatty liver, we performed whole exome sequencing which revealed a novel homozygous mutation in the leptin receptor (p.S389N) that is predicted to be deleterious. Compared to other reported cases with LR mutations, our patient did not report excessive appetite and denied frequent childhood infections. Further workup showed low fasting leptin, 4.2 ng/ml (8.0-38.9 ng/ml for women with BMI 25-30s), fasting glucose of 114mg/dl and insulin of 21 ulU/ml. IGF-I was 141 ng/ml, FSH 4.6 mIU/mL, LH 3.8 U/ml, estradiol 60 pg/Ml, free testosterone 2.1 pg/ml, TSH 2.67 mlu/l, fT4 1.3ng/dl. Her family history was significant for pancreatitis in mother and maternal grandfather, nonalcoholic steatohepatitis (NASH) in her 14-year-old son and liver problems in her sister, but so far, no other members have been tested for the mutation. She was treated with fenofibrate for hypertriglyceridemia with subsequent decrease of Tg levels to 503 mg/dl. Conclusion Our case is unique in that our patient’s clinical features are less severe in comparison to those reported with other LR mutations. Given that this is a novel homozygous mutation in the Ig region of the LR, and it is predicted to be deleterious, it is still unclear how it relates to her lipodystrophic features and overall clinical presentation. This case highlights the gap in knowledge and the diversity in clinical presentations that may accompany LR mutations and would have been missed if it were not for whole exome sequencing. At the same time, this case raises questions regarding the role of the leptin in hypertriglyceridemia, NASH and NAFL, and to what degree emerging therapies for leptin deficiency can prevent the progression of NASH and NAFL disease, since currently there are no clear therapeutic guidelines.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i’s) are the newest class of anti-hyperglycemic drugs. Their mechanism of action involves increasing urinary glucose excretion by preventing glucose reabsorption in the proximal renal tubules, yet they can also promote ketogenesis under certain circumstances. Numerous reports suggest an association between SGLT2i’s and diabetic ketoacidosis (DKA), but the medical literature remains sparse. Since the use of these drugs for diabetes has increased dramatically due to favorable cardiac outcomes, identification of patients at greatest risk for this life-threatening complication is essential. Therefore, in an effort to better understand the circumstances in which SGLT2i associated DKA occurs we reviewed all available cases at our hospital over a 5-year period. Patients and Methods: We retrospectively reviewed all cases of ketoacidosis associated with SGLT2i use at our hospital from 2013 to October 2018 using an electronic medical record search algorithm. Terms included canagliflozin, dapagliflozin, empagliflozin, SGLT2 inhibitors, metabolic acidosis, ketoacidosis, diabetes, and DKA. Patients that developed DKA without being treated with SGLT2i were excluded. Results: We identified 77 cases, 21 of which met criteria for DKA associated with SGLTi use. 64% were female and 36% were male, average age was 57.8 years, BMI 29.8 kg/m2, and mean diabetes duration was 11 years. The majority carried diagnoses of T2DM (94%) and 83.4% had no history of DKA prior to using an SGLT2i. The most common presenting symptoms were nausea, vomiting (38%), abdominal pain (28.5%) and altered mental status (19%). Common precipitants were poor oral intake (57.14%) and infection (23.8%). Average blood glucose concentrations at presentation were 329 + 36 mg/dl, interestingly, 52% of the episodes were euglycemic DKA (euDKA) with blood glucose

Background: Thyrotoxicosis is a known cause of atrial arrhythmias however, ventricular arrhythmias in this setting are rare. We report a case of ventricular fibrillation (VF) in a patient with Graves hyperthyroidism in the absence of coronary disease. Clinical Case: A 55-year old woman with hypertension and a self-reported thyroid nodule presented with a two week history of general malaise, palpations, diarrhea and muscle aches. Her mother had a goiter and paternal aunt required a thyroidectomy. Both her father and paternal uncle died at age 58 and 60 respectively of myocardial infarction. She was tachycardic to 125 beats per minute (bpm) and had a firm goiter with no bruit and normal reflexes. TSH was 6.99 ng/dL (n= 0.7-2.19 ng/dL), total T3 > 7.81 ng/mL (n=0.97 -1.7 ng/mL), thyroid stimulating immunoglobulin 516 % (n= 7.81 ng/mL despite therapy but her heart rate was better controlled at 100 bpm. However, that night she suffered a 40- minute cardiac arrest from VF. Spontaneous circulation was restored after multiple shocks, amiodarone and lidocaine, and then temporary pacing for bradycardia. She received a total of 440mg of propranolol and 40mg of methimazole prior to cardiac arrest. Serum potassium was normal pre arrest but rose to 6.9 mmol/L (n=3.5-5.1 mmol/L) after. Given the bradycardia, glucagon was given for possible beta blocker toxicity although this was thought to be unlikely as telemetry did not reveal pre-arrest bradycardia. There was no evidence of a coronary event since admission troponin was negative and post arrest troponin was only mild elevated with a flat trend. No wall motion abnormality was see on echocardiogram and ventricular function was preserved. Cardiac catheterization was deferred due to declining renal function. Subsequent myocardial perfusion imaging displayed only an apical cap artifact and coronary CT angiogram was free from atherosclerosis. She had no further arrhythmias. An implantable cardioverter defibrillator was placed prior to discharge for secondary prevention of ventricular arrhythmias. Conclusion: VF in the absence of underlying coronary disease or heart failure is rare in thyrotoxicosis. Thyroid hormone induced coronary vasospasm and activation of regionally varied beta-adrenergic receptors are proposed mechanisms for VF. Further, some individuals may have genetic predisposition to this in the setting of hyperthyroidism. This case highlights the urgency of achieving a euthyroid state and closely monitoring individuals with a family or personal history of ventricular arrhythmias or sudden cardiac death.

Background: Macroprolactinomas are normally managed with dopamine agonists, resulting in tumor shrinkage and normalization of prolactin. Occasionally they can invade the skull base, erode the sellar floor, and extend into the sphenoid sinuses. Rarely, dopamine agonist therapy can result in spontaneous CSF leak and rinorrhea. We present a case of cabergoline associated CSF leak. Case Presentation: A 46 y.o. man was diagnosed with a macroprolactinoma after evaluation of fatigue associated with low testosterone. He denied headaches and his gross visual fields were intact. His prolactin was 4916 ng/mL (nl 4-15.2 ng/mL) and MRI showed a large sellar and suprasellar mass, 2.5 x 3.5 x 3.1 cm, extending into the interpeduncular cistern and cavernous sinus while compressing the optic chiasm and right cerebral peduncle. He was started on Carbergoline 0.5 mg, 5 days a week for 2 weeks, then 4 days a week. His serum prolactin declined to 291 ng/mL in 4 weeks. He reported having headaches on the days when he took it but denied rhinorrhea or visual field changes. Two months after treatment began he noticed clear fluid draining from his left nare. It was intermittent and occurred with head movement. He denied headache, photophobia, or neck stiffness. He was instructed to go to the ED for suspicion of a CSF leak. On examination, clear drainage was observed from his left nare. CT and MRI showed shrinkage of the macroprolactinoma with CSF filling the space, and a clear path connecting brain and sinuses, allowing for flow of CSF. Rhinorrhea was collected and sent for glucose, protein, and beta 2 transferrin. Glucose was elevated at 79mg/dL (nl 40-70 mg/dL), protein elevated to 78.4mg/dL (nl 15-45 mg/dL) with beta 2 transferrin detected (nl undetectable). Neurosurgery and ENT evaluation revealed evidence that the prolactinoma had put pressure on his sinuses with resulting bone remodeling allowing communication between his brain and sinuses. This allowed CSF to flow freely through the left nare once the pressure of the prolactinoma was released and space was replaced with CSF. He underwent endoscopic resection of his pituitary tumor, bilateral nasal endoscopy with repair of the CSF leak, and a fat graft. Conclusion: Cabergoline induced CSF rhinorrhea is a rare but life-threatening complication carrying a high risk of ascending meningitis. It can occur within the first few weeks to several months of treatment, and it may be misdiagnosed as allergic rhinitis, sinusitis or the common cold. CSF rhinorrhea can be differentiated from other conditions by fluid analysis for glucose and beta-2 transferrin. Close follow-up and high suspicion for CSF leak should be maintained in patients with invasive prolactinomas where the tumor may be more likely to affect bony architecture.

Background: AMP-activated protein kinase (AMPK) is implicated in several aspects of lipid metabolism including the suppression of de novo lipogenesis, promotion of fatty acid oxidation, and regulation of adipose tissue biology. We report a patient with severe hypertriglyceridemia harboring a heterozygous mutation in the PRKAA1 gene which codes for the α1-subunit of AMPK. Clinical case: A 22-year-old Mexican woman with history of morbid obesity and T2DM presented with eruptive xanthomas in the upper and lower extremities, back, and chest. VS:141/80, P 86, RR 20, 122 kg BMI 43.42 kg/m2. She was misdiagnosed on multiple occasions and had been treated with steroids until a biopsy revealed foamy histiocytes consistent with xanthomas. A lipid panel showed Triglycerides 8,513 mg/dl (0-150 mg/dl) Cholesterol 555 mg/dl (0-199 mg/dl) HDL 29 mg/dl (≥ 41 mg/dl) Direct LDL 44 (0-99). There was no family history of hyperlipidemia. After ~24-months of follow-up abnormal lipid levels persisted: Triglycerides 4527-8513 mg/dl (0-150 mg/dl) Cholesterol 408-555 mg/dl (0-199 mg/dl) HDL 22-29 mg/dl (≥ 41 mg/dl). She had microalbuminuria 87.7 mcg/mg (0-29.9 mcg/mg) and an HbA1c of 7.8%. She endorsed depression and was inconsistent with her diet due to insatiable appetite but reported medication compliance. Lipoprotein electrophoresis showed a pattern consistent with type IV Hyperlipoproteinemia. Sequencing of lipid metabolism genes revealed no abnormalities but upon whole exome scanning she was found to have a heterozygous nonsense variant in PRKAA1 (exon4:c.C394T:p.Q132X) which codes for the α1-subunit of AMPK resulting in a premature stop codon. We hypothesize that this variant results in defective AMPK activity, and given the role of AMPK in lipid and adipose tissue metabolism, it may result in disinhibition of lipogenesis, reduced fatty acid oxidation, and altered adipose tissue biology, together promoting extreme hypertriglyceridemia. Conclusion: This is the first case to implicate a PRKAA1 gene mutation as a cause of severe hypertriglyceridemia in humans.

Introduction Sarcoidosis is a granulomatous disease that can affect multiple organ systems including the central nervous system in 5-15% of patients, yet it is a rare cause of intrasellar lesions (

Introduction: Hypercalcemia is a common clinical problem encountered in hospitalized patients. Mild to moderate hypercalcemia diagnoses may be missed during hospitalization since albumin corrected calcium is not automated with laboratory results. Methods: We performed a retrospective study using total and albumin corrected calcium to identify the prevalence and causes of hypercalcemia in hospitalized patients. Patients with corrected calcium ≥ 10.5 mg/dL were identified by searching the electronic medical records of hospital, from June 2012 to June 2017. Albumin-corrected calcium was calculated with the formula [((4-albumin concentration in g/dl) * 0.8) + Total serum calcium in mg/dl] and data were analyzed using SPSS software. Results: From June 2012 to June 2017 there were 97,900 hospital admissions and 711 cases of hypercalcemia based on total calcium, and 1,067 cases based on corrected calcium, resulting in prevalence rates of 0.73% and 1.09%, respectively. Of the 1067 patients, 86% of patients had mild hypercalcemia (10.5-11.9 mg/dL), 10% had moderate hypercalcemia (12-14 mg/dL) and 4% had severe hypercalcemia (>14 mg/dL). When total calcium was considered, malignancy and hyperparathyroidism accounted for the majority of cases representing 48.2% and 28.6% of cases, respectively, followed by the category of other causes (13.2%). When corrected calcium was used the most common categories of hypercalcemia were malignancy (35.4%), hypercalcemia that was not further evaluated (31.1%), and hyperparathyroidism (22.4%). The overall effect of using corrected calcium was a decrease in the proportion of hypercalcemia cases due to malignancy and hyperparathyroidism from 48.2% to 35.4%, and from 28.6 % to 22.4 %, respectively, but an increase in the proportion of unidentified cases from 10% to 31.1%. 31.1% of patients with hypercalcemia were not further evaluated and no identifiable cause was available, resulting in unexplained hypercalcemia being the second most common category. Overall, the majority of hypercalcemia cases were non-malignant. Conclusion: Our major findings are that the use of albumin corrected calcium resulted in a 49% increase in detection of hypercalcemia cases and that the majority of hypercalcemia cases in hospitalized patients are not associated with malignancy. We suggest that increasing the detection of hypercalcemic disorders by correcting for low albumin is worthwhile in order to achieve better estimates of disease prevalence and to detect potentially deleterious conditions in their earlier stages. We propose the implementation of auto calculated albumin corrected calcium to be displayed with routine laboratory results to increase detection of hypercalcemia cases that may be overlooked due to hypoalbuminemia in hospitalized patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Objective Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by elevated serum calcium with relatively low urinary calcium excretion. It typically results from an altered set point in calcium homeostasis originating from mutations in the calcium-sensing receptor (CASR), AP2S1, or GNA11 genes, which encode for the calcium-sensing receptor (CaSR), adaptor-related protein complex 2, and G-protein alpha-11 subunit, respectively. Despite numerous reports of novel variants in these genes associated with FHH, new variants continue to be discovered. Methods We describe a 20-year-old man with a family history of hypercalcemia who had clinical findings compatible with FHH and no evidence of multiple endocrine neoplasia who underwent CASR gene sequencing for evaluation of hypercalcemia. Parathyroid gland single-photon emission computerized tomography scan was normal. Results CASR gene sequencing revealed a previously unreported heterozygous intronic variant at position 1608+3A>G (chromosome 3: 121994892) resulting in a 77-residue deletion. His mother has a history of bipolar disorder and hyperparathyroidism with an adenoma found on imaging, yet our patient had no evidence of adenoma and therefore no surgical intervention was recommended. Given that CaSR plays a role in parathyroid growth, some variants in CASR may ultimately lead to parathyroid hypertrophy and be mistaken for primary hyperparathyroidism. Conclusion Long-term clinical follow up will be helpful in understanding the ultimate effects of specific CASR mutations on parathyroid growth or progression to significant hypercalcemia.

BackgroundSevere hypoglycaemic events (HGEs) in hospitalised patients are associated with poor outcomes and prolonged hospitalization. Systematic, coordinated care is required for acute management and prevention of HGEs; however, studies evaluating quality control efforts are scarce.ObjectiveTo investigate the effectiveness of system-based interventions to improve management response to HGEs.MethodsSystem-based interventions were designed and implemented following a root cause analysis of HGE in adult patients with diabetes from two general medical wards with the highest incidence of HGE. Interventions included electronic medical record programming for a standardised order set for basal-bolus insulin regimen and hypoglycemia protocol, automated dextrose order, automated MD notification, and recommendation for endocrine consultation after two critical HGEs. The Pyxis MedStation was programmed to alert nurses to recheck blood glucose 15 min after the treatment. A card with the HGE management protocol was attached to each provider’s ID badge and educational seminars were given to all providers.Main outcomes and measuresPrimary outcomes were to evaluate median time from HGE (glucose 100 mg/dL), and time from HGE to follow-up finger-stick (FS) testing preintervention and postintervention. Secondary outcomes were cumulative incidence of HGEs, recurrent hypoglycemia, rate of physician notification and use of standardised treatments among adults with diabetes on the two general medical wards.ResultsAmong hospitalised adults with diabetes and HGE, median time from HGE to euglycemia declined from 225±46 min preintervention to 87±26 min postintervention (p=0.03). Median time from HGE to next FS testing also declined (76±14 min to 28±10 min, pAmong hospitalised adults with diabetes, incidence of HGE decreased from 12% (35/295) over 3 months (preintervention period) to 6% (37/610) over 6 months (postintervention period) (pConclusionsSystem-based interventions had a clinically important impact on decreasing time from HGE to euglycemia and to next FS testing. This hypoglycemia bundle of care may be applied and tested in other community hospitals to improve patient safety.

Hyperglycemia is the unifying metabolic abnormality for all forms of diabetes mellitus, forming the basis for its diagnosis and treatment. The strong epidemiologic associations between hyperglycemia and the complications of diabetes have given rise to the glucose hypothesis-that the complications of diabetes are caused by hyperglycemia and that they can be prevented by normalizing glucose levels. Herein the authors review the epidemiologic relationships between hyperglycemia and the complications of diabetes, the major trials of glucose lowering, and the extent to which the glucose hypothesis is supported by these studies and how this information can be translated into clinical practice.

ObjectiveSevere hypoglycemia (blood glucose < 50 mg/dl) in hospitalized patients with diabetes mellitus is associated with poor outcomes such as increased mortality and readmission rates. We study the effects of system based interventions in managing severe hypoglycemia and its impact on outcomes.Research design and methodsWe performed retrospective review of pre- and post- intervention study to quantify severe hypoglycemia in patients admitted in the general internal medicine wards with primary or secondary diagnosis of diabetes mellitus based on ICD-9 and ICD-10 codes. We implemented multidisciplinary interventions including standardization of treatment, education of in-patient medical teams and physician notification and feedback immediately after severe hypoglycemia. The endpoints were the comparative analysis of incidence of severe hypoglycemia, in-patient mortality rate, 30-day mortality rate, 30-day readmission rate, recovery time from hypoglycemia, time to next glucose measurements, use of standardized treatment and physician notification rate pre-and post-intervention.ResultsThe incidence of severe hypoglycemia per patient with diabetes was reduced from 9.6% (233/2416) to 5.6% (202/3607) (pConclusionsOur study shows that multidisciplinary strategies improves the process of early detection and management of severe hypoglycemia and reduce incidence and in-patient mortality rate.

As the pandemic of type 2 diabetes spreads globally, clinicians face many challenges in treating an increasingly diverse patient population varying in age, comorbidities, and socioeconomic status. Current therapies for type 2 diabetes are often unable to alter the natural course of the disease and provide durable glycemic control, and side effects in the context of individual patient characteristics often limit treatment choices. This often results in the progression to insulin use and complex regimens that are difficult to maintain. Therefore, a number of agents are being developed to better address the pathogenesis of type 2 diabetes and to overcome limitations of current therapies. The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects. These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-β-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade. Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations.

Genome-wide array studies have associated the patatin-like phospholipase domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or a lipogenic enzyme and whether PNPLA3 is involved in the pathogenesis of hepatic insulin resistance. To address these questions we treated high-fat-fed rats with specific antisense oligonucleotides to decrease hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could be attributed to decreased fatty acid esterification measured by the incorporation of [U-13C]-palmitate into hepatic triglyceride. While the precursors for phosphatidic acid (PA) (long-chain fatty acyl-CoAs and lysophosphatidic acid [LPA]) were not decreased, we did observe an ∼20% reduction in the hepatic PA content, ∼35% reduction in the PA/LPA ratio, and ∼60%-70% reduction in transacylation activity at the level of acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase. These changes were associated with an ∼50% reduction in hepatic diacylglycerol (DAG) content, an ∼80% reduction in hepatic protein kinase Cε activation, and increased hepatic insulin sensitivity, as reflected by a 2-fold greater suppression of endogenous glucose production during the hyperinsulinemic-euglycemic clamp. Finally, in humans, hepatic PNPLA3 messenger RNA (mRNA) expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic role of PNPLA3 in humans. Conclusion: PNPLA3 may function primarily in a lipogenic capacity and inhibition of PNPLA3 may be a novel therapeutic approach for treatment of nonalcoholic fatty liver disease-associated hepatic insulin resistance. ((Hepatology 2013;57:1763-1772))

There is growing evidence suggesting that high-density lipoprotein (HDL) function is more important than the HDL cholesterol (HDL-C) levels. HDL particles are highly heterogeneous and their function may also differ among different patient populations. There are two populations that are recognized tohave significant residual cardiovascular risk despite intensive statin therapy: atherogenic dyslipidaemia and diabetes mellitus. Atherogenic dyslipidemia and diabetes have significant homology with regards to lipid profiles. However, systemic epidemiological studies that describes the overlapping profiles between atherogenic dyslipidemia and diabetes is lacking. The function and types of HDL in these two populations needs to be carefully elucidated. HDL has many functions includingreverse cholesterol transport, anti-oxidant activity and anti-inflammatory activity. HDL may also exert “antiplatelet effects”but the mechanism is unclear.We assessed the prevalence of atherogenic dyslipidemia in diabetes mellitus using data from the National Health and Nutrition Examination Survery (NHANES) and data from Yale New Haven Health (YNHH). We found that atherogenic dyslipidemia and diabetes mellitushave overlapping lipid profiles but are clearly two distinct conditions. In our preliminary studies, we found that HDL inhibits platelet aggregation and activation. Very interestingly, we found HDL can induce mitochondria dependent platelet apoptosis. The antiplatelet effect of HDL, as observed by others in the past, may arise fromapoptotic platelets that do not aggregate, and thus the inhibition of platelet aggregation. Whether HDL subtypes from atherogenic dyslipidemia and diabetes patient have differential effects on platelet apoptosis are currently being investigated.

Diabetes affects a large and diverse number of individuals who share in common its risks for complications but who differ greatly from one another in age, health, and a number of circumstances influential to successful treatment. Because type 2 diabetes comprises the majority of diabetes cases, a number of agents have been developed for its treatment. Their unique properties offer opportunities to overcome some of the treatment limitations of older medicines and enable a more individualized and flexible approach to glucose-lowering. At the same time, new medications are accompanied by greater costs and uncertainties about their long-term benefits or safety, and thus the present state of care for type 2 diabetes places focus on a process of shared decision-making between the clinician and patient as to which treatments can optimize health while minimizing harms. We review the major classes of diabetes agents and provide some guidance for how one might approach decision-making in choosing among them.

Although mutations in the Wnt/β-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2′-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of β-catenin. β-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. β-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. β-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCε activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing β-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.—Popov, V. B., Jornayvaz, F. R., Akgul, E. O., Kanda, S., Jurczak, M. J., Zhang, D., Abudukadier, A., Majumdar, S. K., Guigni, B., Petersen, K. F., Manchem, V. P., Bhanot, S., Shulman, G. I., Samuel, V. T. Second-generation antisense oligonucleotides against β-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.

A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-(13)C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2'-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.

Hyperglycemia is the unifying metabolic abnormality for all forms of diabetes mellitus, forming the basis for its diagnosis and treatment. The strong epidemiologic associations between hyperglycemia and the complications of diabetes have given rise to the glucose hypothesis-that the complications of diabetes are caused by hyperglycemia and that they can be prevented by normalizing glucose levels. Herein the authors review the epidemiologic relationships between hyperglycemia and the complications of diabetes, the major trials of glucose lowering, and the extent to which the glucose hypothesis is supported by these studies and how this information can be translated into clinical practice.

We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat–fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes.

Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2α signaling, together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2α (eIF2α-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2α-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2α. Inhibition of the eIF2α-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2α inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2α. Together, these data imply that the hepatic ER stress eIF2α signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2α-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2α is crucial for proper resolution of insulin-induced ER stress.

In this issue, Esposito and colleagues and Qayyum and coworkers evaluate the potential roles of newer insulin analogues for treating type 2 diabetes. In making the transition from oral therapies to...